Transformation of π-conjugated macrocycles: from furanophanes to napthalenophanes

Applying sequential Diels–Alder cycloaddition and deoxygenation to small π-conjugated furan macrocycles fully converts them to 1,4-naphthalophanes with either ethylene or acetylene spacers, depending on the reaction conditions. 1,4-Napthalenophane tetraene exhibits a 1,3-alternating conformation in the solid state, inclusion of solvent molecules within the macrocycle, and low reduction potentials.


Materials and Methods:
All reagents and chemicals were obtained from commercial suppliers and used as received without further purification. Flash chromatography (FC) was performed using CombiFlash SiO2 columns. 1 H and 13 C NMR spectra were recorded in solution on a Brucker-AVIII 400 MHz and 500 MHz spectrometers using tetramethylsilane (TMS) as the external standard. The spectra were recorded using chloroform-d, benzene-d and dichloromethane-d as the solvents. Chemical shifts are expressed in δ units. High resolution mass spectra were measured on a HR Q-TOF LCMS and Waters Micromass GCT_Premier Mass Spectrometer using ESI.

S2. Syntheses and Characterization
Scheme S1. Synthetic scheme for the preparation of macrocycles 1 and 2.

Synthesis of 4:
To a solution of 2-(trimethylsilyl)phenyl trifluoro-methanesulfonate (0.3 mL, 1.2 mmol) and 1,2-di(furan-2-yl)ethyne (0.1 g, 0.3 mmol) in acetonitrile (MeCN, 2 mL) was added finely powered anhydrous CsF (0.8 g, 5.5 mmol) and the mixture was stirred at room temperature for 12 hours. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel using 20% ethyl acetate in hexane to give 4 as a white solid (82 mg, 264.2 mol, 83.6%).

S5
To a solution of 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.3 mL, 1.2 mmol) and 5 (0.1 g, 0.3 mmol) in MeCN (2 mL) and ethyl acetate (1 mL) was added finely powered anhydrous CsF (0.8 g, 5.5 mmol) and the mixture was stirred at room temperature for 12 hours. The resulting mixture extracted with ethyl acetate. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel using 30% ethyl acetate in hexane to give the 6 as a yellow solid that was used without further purification. HRMS (ESI) m/z: [M+H] + Calcd for C48H28O4 669.2060; found 669.2065.

Synthesis of 1
At 0 o C, TiCl4 (0.5 mL, 2.1 mmol) was progressively added to a suspension of zinc dust (0.39 g, 5.9 mmol) in anhydrous tetrahydrofuran (THF, 10 mL) under argon. The resulting mixture was heated to reflux and kept there for 10 minutes. A solution of 5 cycloadduct (0.1 g, 0.15 mmol) in anhydrous THF (5 mL) was added dropwise over 2 hours while maintaining the temperature at 0 o C using an ice-water bath. The reaction mixture was then refluxed for 15 hours. After cooling, the reaction mixture was poured into 100 g of crushed ice and extracted by CH 2 Cl 2 . The organic layer was washed with water and brine, dried (MgSO 4 ), and concentrated under reduced pressure. The residue thus obtained was purified by flash column chromatography on silica gel using 20% ethyl acetate in hexane to give 1 as slight yellow solid (5 mg, 8.2 mol, 5%).

S6
The solution of the 5 (0.1 g, 0.15 mmol) and anhydrous sodium iodide (0.09 g, 0.6 mmol) in dry MeCN (2 mL) was treated with trimethylsilyl chloride (0.08 mL, 0.6 mmol) at 0 o C under argon and stirred for 12 hours. The reaction was quenched by adding of 2 mL of 5% aqueous Na2S2O3. The resulting mixture was then extracted with dichloromethane. The organic layer was washed with 5% aqueous Na2S2O3 (2 mL), brine (5 mL), dried (MgSO4) and and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by flash column chromatography on silica gel using 20% ethyl acetate in hexane to give 2 (15 mg, 24.8 mol, 16.6%).

S5. Computational Results
All calculations were carried out with the Gaussian16 series of programs [1] using density function theory (DFT). Becke's threeparameter exchange functional combined with the Lee-Yang-Parr correlation functional (B3LYP) and with the 6-31G(d) basis set was used for all calculations. No symmetry restrictions were applied in any of the optimal geometries presented. The optimal geometries for all structures were confirmed as minima by frequency calculations. No negative frequencies were found for any stationary points presented in this work. The discussion of 1 and 2 in this work focuses on their most stable conformations. However, each can adopt several conformations other than the optimal ones and therefore we present these conformers, the terminology used to describe them and their absolute energies. Due to the similarity in the possible conformations, we chose to use and modify the terminology used to describe calixarenes. While this terminology can be applied as-is to 1 (Figure S22), to describe 2 we added an additional description to the 1,2-alternating conformer to denote the linker that separates the naphthalenes involved; 1,2-Et is used when the separator is an ethylene, and 1,2-Ac is used when an acetylene separates between the naphthalenes ( Figure S23). The energies where calculated using B3LYP/6-31G(d) in three different ways: without and additional parameters (Table S3), with the GD3 dispersion correction (Table S4), and using both the GD3 dispersion correction and the CPCM model to simulate solvation in chloroform (   Table S5).

S5.3. Strain Energies
The ring strain for both 1 and 2 was calculated using a homodesmotic chemical equation as shown below.
Scheme S2. Bond separation equations and energies calculated at the B3LYP/6-31G(d) level of theory.

S5.4. Transition States
All transition states were optimized using the QST3 method in the Gaussian16 series of programs using the same basis and functional as the stationary point optimizations (DFT/B3LYP/6-31G(d)) and confirmed by the presence of a single imaginary frequency in the range of (-235)-(-245) cm -1 along the reaction coordinate of the cycloaddition.
Due to the four cycloadditions required to transform 5 to 6 it is highly likely that multiple isomers and diastrioisomers will form.
To simplify the mapping process of the transformation we assumed that due to sterical reasons each cycloaddition was more likely to occur on the side of the ring plane opposite to the closest transformed furan (anti). We then calculated the energy barriers and relative stabilities for each pathway to locate the kinetic and thermodynamically favorable pathways. For each cycloaddition one position will be favored kinetically (lowest energy barrier) and another will be favored thermodynamically (most stable product), but in all cases the energy differences between the kinetic and thermodynamic pathways are always lower than 1 kcal mol -1 (Table S8). This leads us to conclude that while several pathways will be more favorable than others, no single pathway will dominate any of the stages of the cycloadditions and that multiple intermediates are likely to form while the reaction takes place. Figure S24. First cycloaddition of benzyne to 5 to form the product I. Not to scale. S27 Figure S25. Second cycloaddition of benzyne to I to form the products II-1, II-2 and II-3. The pathway leading to and from II-3 was discontinued as it is the least favorable both kineticaly and thermodynamicaly. Not to scale.
S28 Figure S26. Third cycloaddition of benzyne to II-1 to form III-1. Not to scale. Figure S27. Third cycloaddition of benzyne to II-2 to form III-2 and III-3. Not to scale. Figure S28. Fourth cycloaddition of benzyne to III-1, III-2 and III-3 to form 6. The energy of the transition state between III-2 to 6 and III-3 to 6 is identical. Not to scale.

S5.5. NICS and ACID Calculations
Nucleus-independent chemical shifts (NICS) calculations can be used to estimate the aromaticity based on the existence and effect of a ring current; negative NICS values inside a ring may indicate aromaticity, whereas positive values point toward an antiaromatic system.

S5.6.1 NICSzz
To probe the global effects of aromaticity and antiaromaticity we used the standard NICS operating method, i.e. placed dummy atoms in 1 Å above and below that dummy atom in relation to the plane. The dummy atoms were placed in plane, and 1 Å above and below the plane for each of the rings (1, and 2) as described in the Figure 29.

S31
In NICS(1)zz the dummy atoms face the inner surface of the macrocycle and NICS(-1)zz they face the outer surface. Therefore, global antiaromaticity should result in the deshielding of the inner protons (NICS(1)zz) and shielding of the outer protons (NICS(-1)zz). If global ring current was a prominent factor, the values for outer 1 should be more negative than that of ring 2 (Table S10).
On first sight, it does indeed seem that there is small difference between the inner and outer dummy atoms (NICS(1)zz vs NICS(-1)zz). However, since such difference can also be affected by the sigma bonds of neighboring rings, we compared it with the same macrocycles with "broken" conjugation (Table S11), that is after replacing one double bond with a single bond. If the effect between the inner and outer NICS values is indeed due to global aromaticity, it should not be expressed in these structures. As can be observed, the difference between the NICS(1)zz and NICS(-1)zz remain the same for either the fully-conjugated macrocycles in Table 10 and the macrocycles with one double bond replaced with a single bond (Table 11). We can therefore conclude that NICS calculations do not show global ring current in the neutral macrocycles.  Overall, the NICS and AICD calculations indicate no global ring currents for 1 and 2 in their neutral forms. This validates our original assumption, that the difference in chemical shifts does not stems from global aromaticity.
We note that while global aromaticity is not commonly observed neutral macrocycles their neutral state, it was observed in the charged (dianion) state. Thus, the interplay reported previously was between local aromaticity in the neutral state and globa l aromaticity for dianions. Indeed, ACID and NICS calculations performed on dicationic macrocycles show that they are globally aromatic:

S33
As can be observed, the difference in NICS values between internal and external dummy atoms varies by 8 ppm, indicating a strong global current. Acid plots for 1 +2 and 2 +2 also show a clear aromatic (clockwise) current. Figure S31. ACID plot for the dications 1 -2 (left) and 2 -2 (right), calculated using B3LYP /6-31G(d).
From these calculations, we can conclude that while for the neutral macrocycles, no global aromaticity can be observed for an y of the conformers, and therefore global effect cannot explain the variation in NMR chemical shifts. However, upon reduction, global (anti)aromaticity is significant, which can partially explain the difference in reduction potentials.

S5.5.2. 3D NICS Maps
To better represent the NICS values inside the macrocycles we plotted a heat map representing the NICSzz values at Z = 0 across the X-Y plane. Positive values appear in read, and negative values appear in blue. All calculations were performed using B3LYP/6-31G(d).
S34 Figure S32. NICSzz map at Z = 0 across the X-Y plane of the 1,3 alternate conformer of 1. Figure S33. NICSzz map at Z = 0 across the X-Y plane of the cone conformer of 1. Figure S34. NICS zz map at Z = 0 across the X-Y plane of the 1,2-Ac alternate conformer of 2. Figure S35. NICSzz map at Z = 0 across the X-Y plane of the cone conformer of 2.

S6. Electrochemistry
For electrochemical measurements, 1,2-dichloroethane (DCE) containing 0.1 M tetra-n-butylammonium hexafluorophosphate (TBAPF6) was used as a solvent. An Ag/AgCl quasi-reference electrode was prepared by dipping a silver wire in an aqueous solution of FeCl3 and HCl. Platinum-disk and platinum-wire electrodes were applied as working and counter electrodes, respectively. All electrochemical measurements were externally calibrated against the E1/2 of the Fc/Fc + redox couple. Redox potentials were determined as the halfway potentials between the reduction and oxidation peaks (E1/2). Figure S36. Cyclic voltammetry of 2 (cyan) and 1 (blue) in DCE as solvent and 0.1 M TBAPF6 as electrolyte, referenced against the Fc/Fc + redox couple (scan rate 100 mV/s).